Capsaicin receptor TRPV1 maintains quiescence of hepatic stellate cells in the liver via recruitment of SARM1.

BACKGROUND & AIMS: Capsaicin receptor, also known as transient receptor potential vanilloid 1 (TRPV1), is involved in pain physiology and neurogenic inflammation. Herein, we discovered the presence of TRPV1 in hepatic stellate cells (HSCs) and aimed to delineate its function in this cell type and liver fibrosis. METHODS: TRPV1 expression was examined in liver biopsies from patients with liver fibrosis using quantitative real-time PCR and immunostaining. Its contribution to liver fibrosis was examined in Trpv1-/- mice, upon lentiviral delivery of the TRPV1 gene, and in human and mouse primary HSCs, using patch clamp, intracellular Ca2+ mobilization determination, FACS analyses and gain/loss of function experiments. Binding of sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) to TRPV1 was determined using mass spectrometry, co-immunoprecipitation, surface plasmon resonance, bioluminescence resonance energy transfer, and NanoBiT. RESULTS: TRPV1 mRNA levels are significantly downregulated in patients with liver fibrosis and mouse models, showing a negative correlation with F stage and α-smooth muscle actin expression, a marker of HSC activation. TRPV1 expression and function decrease during HSC activation in fibrotic livers in vivo or during culture. Genetic and pharmacological inhibition of TRPV1 in quiescent HSCs leads to NF-κB activation and pro-inflammatory cytokine production. TRPV1 requires binding of its N-terminal ankyrin repeat domain to the TIR-His583 (Toll/interleukin-1 receptor) domain of SARM1 to prevent HSCs from pro-inflammatory activation. Trpv1-/- mice display increased HSC activation and more severe liver fibrosis, whereas TRPV1 overexpression is antifibrotic in various disease models. CONCLUSION: The antifibrotic properties of TRPV1 are attributed to the prevention of HSC activation via the recruitment of SARM1, which could be an attractive therapeutic strategy against liver fibrosis. IMPACT AND IMPLICATIONS: We identified the neuronal channel protein TRPV1 as a gatekeeper of quiescence in hepatic stellate cells, a key driver of liver fibrogenesis and chronic liver disease. Physiologically expressed in healthy liver and consistently downregulated during liver fibrosis development, its therapeutic re-expression is expected to have few side effects, making it an attractive target diagnostic tool and drug candidate for industry and clinicians.

Depression is associated with worse outcome after percutaneous endoscopic lumbar discectomy: a 5-year follow-up study.

This study aimed to investigate the relationship between depression and outcome of percutaneous endoscopic lumbar discectomy (PELD) in patients with lumbar disc herniation. We examined 268 patients who underwent PELD for lumbar disc herniation and were followed for five years. Patients were grouped according to mood: normal mood (159 patients) and continuous depression (109 patients). Depressive symptoms were assessed using the 21-item Beck Depression Inventory. Back and leg pain were assessed using the visual analogue scale. Subjective disability was measured using the Oswestry Disability Index. Neurological function and physical disability were assessed using the Japanese Orthopaedic Association score. Disc-height ratio and intervertebral instability were measured to assess lumbar stability. Clinical and radiological data were recorded before surgery and at the 3-month, 6-month, 1-year, 2-year, and 5-year follow-ups. Although the Japanese Orthopaedic Association, visual analogue scale, and Oswestry Disability Index scores did not significantly differ between groups before surgery, all three scores significantly differed between groups at all follow-up time points after PELD (p < 0.05). Measurements of disc-height ratio and intervertebral instability did not significantly differ between the groups before surgery nor at any point after surgery (P > 0.05). Patients with continuous depression exhibited less improvement in symptom severity and disability score after PELD at all time points in the five years after surgery. Depression had little effect on lumbar vertebral stability after PELD. Interventions to detect and treat depression should be performed before and after surgery.

Development of an extended STIRPAT model to assess the driving factors of household carbon dioxide emissions in China.

Although the past twenty years have witnessed China's remarkable economic development, the cost in terms of greenhouse gas emissions and a deteriorating environment has been enormous. Numerous studies have revealed the influence of household factors on household carbon dioxide emissions (HCEs) and called for a reduction of HCEs to mitigate climate change, but few have focused on assessing the most significant household driving factors of HCEs. Using statistical data between 2005 and 2019 in Jiangsu, China, this study developed an extended stochastic impact by regression on population, affluence, and technology (STIRPAT) model to assess the most significant driving factors of HCEs. The results show that the most significant driving factors are household size, total population, unemployment, and urbanisation rate. The study found that HCEs are positively impacted by household size while negatively impacted by the unemployment rate. Based on the study's findings, the following suggestions are proposed to lower HCEs: (i) establish an optimal consumption concept to guide residents towards consuming reasonably; (ii) cultivate a low-carbon concept among residents and promote low-carbon emissions living; and (iii) pay close attention to population structure factors and formulate effective measures accordingly. The study provides insightful information on the key driving factors of HCEs, which can facilitate achieving carbon emissions neutrality.

Surface salt bridges contribute to the extreme thermal stability of an FN3-like domain from a thermophilic bacterium.

This study uses differential scanning calorimetry, X-ray crystallography, and molecular dynamics simulations to investigate the structural basis for the high thermal stability (melting temperature 97.5°C) of a FN3-like protein domain from thermophilic bacteria Thermoanaerobacter tengcongensis (FN3tt). FN3tt adopts a typical FN3 fold with a three-stranded beta sheet packing against a four-stranded beta sheet. We identified three solvent exposed arginine residues (R23, R25, and R72), which stabilize the protein through salt bridge interactions with glutamic acid residues on adjacent strands. Alanine mutation of the three arginine residues reduced melting temperature by up to 22°C. Crystal structures of the wild type (WT) and a thermally destabilized (∆Tm -19.7°C) triple mutant (R23L/R25T/R72I) were found to be nearly identical, suggesting that the destabilization is due to interactions of the arginine residues. Molecular dynamics simulations showed that the salt bridge interactions in the WT were stable and provided a dynamical explanation for the cooperativity observed between R23 and R25 based on calorimetry measurements. In addition, folding free energy changes computed using free energy perturbation molecular dynamics simulations showed high correlation with melting temperature changes. This work is another example of surface salt bridges contributing to the enhanced thermal stability of thermophilic proteins. The molecular dynamics simulation methods employed in this study may be broadly useful for in silico surface charge engineering of proteins.

Neurotrophic factors stimulate the activation of hepatic stellate cells in liver fibrosis.

BACKGROUND AND AIMS: Patients with liver fibrosis who have pain in the liver region may have changed nerve factors. The expression of neurokines and hepatic nerves in liver fibrosis, however, was little understood. In order to better understand how liver fibrosis develops, we plan to look into the hepatic nerve and neurokine changes and how they relate to hepatic stellate cells (HSCs). METHODS: The expression of neurokines in liver samples from 55 chronic hepatitis B patients and the carbon tetrachloride (CCl4) animal model were studied. The co-staining of Nissl and α-SMA allowed us to investigate the neurons and their interaction with α-SMA in fibrotic livers, as well as the expression of the glial cell marker glial fibrillary acidic protein (GFAP) and its relationship with α-SMA, a marker of HSCs. SH-SY5Y cells were treated with a fibrotic serum to imitate the hepatic microenvironment on neuronal cells. We also used brain-derived neurotrophic factor (BDNF) to stimulate mouse primary HSCs and LX2. RESULTS: The levels of mRNA for neurokines such as BDNF, GFAP, and growth-associated protein (GAP43) are significantly increased in both human and animal liver fibrosis. As liver fibrosis advances, we found that Nissl bodies and α-SMA may co-localize, suggesting a connection between hepatic nerves and HSCs. Human fibrotic serum may increase neurkines, notably BDNF, in SH-SY5Y cells. We also found that BDNF increased pro-inflammatory cytokines and fibrogenic markers in hHSCs. CONCLUSIONS: Patients with hepatic fibrosis had significantly higher levels of BDNF, GFAP, GAP43, and nerve fibers. HSC and nerve fibers interact, and nerves also create neurogenic substances that promote liver fibrosis and HSC activation.

Glial cell line-derived neurotrophic factor contributes to alcoholic-induced liver injury by regulating the NF-κB pathway.

BACKGROUND: Alcoholic liver disease (ALD) is associated with high morbidity and mortality worldwide. The pathogenesis of ALD is not completely understood. Although accumulating evidence suggests an important role of glial cell line-derived neurotrophic factor (GDNF) in several diseases, there are no data concerning its role in ALD. This study compared patients with ALD with control subjects and used a mouse model and a cell culture model to investigate the function of GDNF in ALD and its mechanism of action in hepatocyte injury. METHODS: Serum levels of GDNF were measured in 25 patients with ALD and 25 healthy control subjects. A 4-week Lieber-DeCarli ethanol (EtOH) liquid diet combined with the Gao-Binge model was used in the mouse study. Mouse primary hepatocytes and Huh-7 cells were used for cell experiments. The parameters of liver injury, inflammatory cytokines, and lipid metabolism were measured. RESULTS: Patients with alcoholic hepatitis had higher serum GDNF than control subjects. Expression of GDNF mRNA and protein was markedly increased in mice in the chronic-plus-binge ALD mouse model. The level of GDNF mRNA was upregulated in primary hepatic stellate cells isolated from ethanol-fed mouse liver. Ethanol induced GDNF expression in LX2 cells. The levels of inflammatory cytokines (tumor necrosis factor α, interleukin 1ß, and monocyte chemotactic protein 1) were significantly increased after GDNF stimulation in primary hepatocytes and Huh-7 cells. After GDNF stimulation, levels of both p-AKT and p-NF-κB were significantly increased in primary hepatocytes and Huh-7 cells. The NF-κB activity induced by GDNF was significantly decreased by an NF-κB inhibitor, which limited hepatocyte injury and inflammation. CONCLUSIONS: The concentration of GDNF is increased in the circulation of ALD patients. GDNF promotes alcohol-induced liver injury and inflammation via the activation of NF-κB, which mediates hepatocyte injury and inflammatory cytokine expression. Based on these findings, GDNF is a potential therapeutic target for preventing or ameliorating liver injury in ALD.

Ferroptosis is involved in the development of neuropathic pain and allodynia.

Neuropathic pain (NP) is chronic, intractable, and typically not alleviated using analgesics. Ferroptosis is a new type of cell death characterized by mitochondrial damage, oxidative stress, and mitochondrial dysfunction, affecting specific types of synaptic plasticity in the spinal cord. Here, we evaluated the role of ferroptosis in NP using chronic contractile injury (CCI) in rats. The CCI and control groups were subjected to sciatic nerve ligation. The mechanical withdrawal threshold and thermal withdrawal reflex latency were used to detect changes in mechanical pain threshold and thermal pain threshold in rats, respectively. Notably, CCI caused mechanical and thermal stimulation of the injured hind paw, reduced levels of glutathione peroxidase 4 (GPX4), and increased acyl-CoA synthetase long-chain family member 4 (ACSL4). Treatment with the ferroptosis inhibitor ferrostatin-1 (10 mg/kg) 1 h after surgery upregulated GPX4 expression and downregulated ACSL4 expression, whereas the ferroptosis inducer, erastin (10 mg/kg), exerted opposite effects. Treatment with ferrostatin-1 upregulated NeuN expression and downregulated GPX4 expression, whereas erastin reversed these effects. CCI increased the number of damaged mitochondria and decreased the mean planar mitochondrial area, and treatment with erastin further exacerbated these effects. The iron ion content in the spinal cords of CCI-induced rats increased. Treatment with ferrostatin-1 decreased, whereas treatment with erastin increased iron ion content in the CCI-induced rat model. Taken together, our results showed that ferroptosis is involved in the development of NP in male rats by blocking neuron and astrocyte activation in the spinal dorsal horn.

Enhanced biomass and cadmium accumulation by three cadmium-tolerant plant species following cold plasma seed treatment.

Cold plasma seed treatment can promote plant growth and enhance the resistance of agricultural crops to adverse stress. However, the effects of plasma seed treatment on the growth and phytoextraction response of plants to cadmium (Cd) remain poorly documented. Here, we have investigated the feasibility of using plasma seed treatment to enhance the biomass and Cd accumulation of three Cd-tolerant species, namely Bidens pilosa L, Solanum nigrum L. and Trifolium repens L, under different plasma treatment conditions. Possible enhancement mechanisms are also proposed according to the levels of organic acids in the roots and the Cd fractions in rhizosphere soil following different plasma treatment conditions. The optimum plasma power was 100 W (B. pilosa) or 500 W (S. nigrum and T. repens). The optimum plasma exposure time for all three species was 60 s. Plasma seed treatment under the optimum treatment conditions enhanced plant dry biomass by ~17.3-45.0% and Cd accumulation by 8.8-54.4% across all three species compared to the controls. Furthermore, the phytoremediation efficiencies, bioaccumulation factors and transfer factors of the three species also increased significantly after seed plasma treatment. The promotion of plasma treatment on the biomass and Cd accumulation of three species might be due to increased exudation of organic acids from the roots into the rhizosphere soil, thus increasing the concentrations of acid-soluble Cd to form Cd-organic acid complexes that facilitated the uptake and translocation of Cd by the plants. Results of this study revealed that cold plasma seed treatment is an environmentally friendly, economical and efficient means to develop the application of phytoremediation for Cd-contaminated soils.

Cardanol-derived cationic surfactants enabling the superior antibacterial activity of single-walled carbon nanotubes.

Single-walled carbon nanotubes (SWCNTs) are potential antibacterial material, and their antibacterial activity in aqueous solutions depends on efficient surfactants to create strong interactions between well-dispersed SWCNTs and bacterial cells. Here, we designed and synthesized a new family of cationic surfactants by introducing different positively charged hydrophilic heads, i.e. -(CH2)6N+(CH3)3Br-, -(CH2)2N+(CH3)3Br- and -(CH2)2N+PyridineBr-, to cardanol obtained from cashew nut shell liquid. These surfactants can efficiently disperse SWCNTs in aqueous solutions because benzene rings and olefin chains in cardanol enable their strong π-stacking on SWCNTs. A much higher fraction of SWCNTs can be dispersed individually compared to the commonly used surfactant, dodecylbenzene-sulfonate sodium (SDBS). SWCNTs dispersed in the cardanol-derived surfactants demonstrate significantly improved antibacterial activity. At the concentration of 0.5 wt%, their minimum inhibitory concentration is 0.33 and 0.02 µg ml-1 against E. coli and S. aureus, respectively, which is only 0.8%-1.5% of that of SDBS-dispersed SWCNTs. The strong antibacterial activity can be attributed to both better dispersion of SWCNTs and positive charges introduced by hydrophilic heads, which are attracted to negatively charged bacterial cell surfaces. These cardanol-derived surfactants are promising as sustainable surfactants for enabling various SWCNT applications.

Pesticide residues in soils planted with Panax notoginseng in south China, and their relationships in Panax notoginseng and soil.

In this study, 73 samples from soils planted with Panax notoginseng and six P. notoginseng samples were collected in Yunnan Province to investigate the residual levels of six pesticides and their relationships with P. notoginseng and soil. All six pesticides were detected in the soils planted with P. notoginseng located in three regions of Shilin, Kaiyuan, and Yanshan. The detection frequencies of the pesticides in the soils followed the order: quintozene (100%) > iprodione (96%) > procymidone (69%) > chlorothalonil (51%) > pyrimethanil (49%) > pyraclostrobin (29%). The median concentrations of iprodione, pyraclostrobin, pyrimethanil, quintozene, procymidone, and chlorothalonil were 46.40, 6.4, 3.1, 2.86, 2.69, and 0.24 µg/kg, respectively. The mean concentrations of pesticides in the three regions followed the order: Kaiyuan > Shilin > Yanshan, except for iprodione. Furthermore, the concentrations of pesticide residues in soils in each region followed the order: soils never planted with P. notoginseng < soils previously planted with P. notoginseng < soils currently planted with P. notoginseng. The concentration of chlorothalonil in P. notoginseng followed the order: root > stem > leaf, whereas those of the other five pesticides followed the opposite order: root < stem < leaf. There were significant positive correlations between the mean concentrations of pesticides in P. notoginseng and those in the corresponding soils. These results indicate that the rational application of pesticides in P. notoginseng cultivation would be effective for reducing the accumulation of pesticides in P. notoginseng to protect people from the harmful effects of residual pesticides.

Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling.

OBJECTIVE: Although glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-ß superfamily, its function in liver fibrosis has rarely been studied. Here, we investigated the role of GDNF in hepatic stellate cell (HSC) activation and liver fibrosis in humans and mice. DESIGN: GDNF expression was examined in liver biopsies and sera from patients with liver fibrosis. The functional role of GDNF in liver fibrosis was examined in mice with adenoviral delivery of the GDNF gene, GDNF sgRNA CRISPR/Cas9 and the administration of GDNF-blocking antibodies. GDNF was examined on HSC activation using human and mouse primary HSCs. The binding of activin receptor-like kinase 5 (ALK5) to GDNF was determined using surface plasmon resonance (SPR), molecular docking, mutagenesis and co-immunoprecipitation. RESULTS: GDNF mRNA and protein levels are significantly upregulated in patients with stage F4 fibrosis. Serum GDNF content correlates positively with α-smooth muscle actin (α-SMA) and Col1A1 mRNA in human fibrotic livers. Mice with overexpressed GDNF display aggravated liver fibrosis, while mice with silenced GDNF expression or signalling inhibition by GDNF-blocking antibodies have reduced fibrosis and HSC activation. GDNF is confined mainly to HSCs and contributes to HSC activation through ALK5 at His39 and Asp76 and through downstream signalling via Smad2/3, but not through GDNF family receptor alpha-1 (GFRα1). GDNF, ALK5 and α-SMA colocalise in human and mouse HSCs, as demonstrated by confocal microscopy. CONCLUSIONS: GDNF promotes HSC activation and liver fibrosis through ALK5/Smad signalling. Inhibition of GDNF could be a novel therapeutic strategy to combat liver fibrosis.

A Predictive Model to Distinguish Papillary Thyroid Carcinomas from Benign Thyroid Nodules Using Ultrasonographic Features: A Single-Center, Retrospective Analysis.

BACKGROUND We developed a model based on ultrasound (US) features of thyroid nodules and cervical lymph nodes to distinguish papillary thyroid carcinomas (PTC) from benign thyroid nodules. MATERIAL AND METHODS We retrospectively collected data on preoperative ultrasonographic characteristics and postoperative histological data from 1119 patients who underwent thyroidectomy in our center from January 2017 to January 2018. Variables of age, sex, and US features of thyroid nodule and lymph nodes features were analyzed. A logistic regression model was established for PTC prediction. RESULTS Logistic regression analysis confirmed that age under 45 years (OR=2.22, p=0.00), hypoechogenicity (OR=3.70, p=0.00), irregular shape (OR=2.13, p=0.004), ill-defined margin (OR=2.26, p=0.08), spiculate margin (OR=3.30, p=0.00), indefinite border (OR=2.45, p=0.00), capsular invasion (OR=7.76, p=0.006), taller-than-wide shape (OR=2.94, p=0.00), solid structure (OR=2.46, p=0.001), microcalcifications (OR=3.92, p=0.00), coexistence of microcalcifications and macrocalcifications (OR=5.84, p=0.006), and central vascularity (OR=2.10, p=0.001) were independently associated with increased risks for PTC, as well as lymph nodes metastasis features (absence of an echogenic hilum [OR=3.74, p=0.027] and increased vascularization [OR=3.55, p=0.086]). The area under the curve (AUC) for the risk score diagnosis system was 0.916. CONCLUSIONS This predictive model is a reliable, simple, and cost-effective diagnostic tool for PTC.

MicroRNA-942 mediates hepatic stellate cell activation by regulating BAMBI expression in human liver fibrosis.

MicroRNA (miRNA)-mediated gene regulation contributes to liver pathophysiology, including hepatic stellate cell (HSC) activation and fibrosis progression. Here, we investigated the role of miR-942 in human liver fibrosis. The expression of miR-942, HSC activation markers, transforming growth factor-beta pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI), as well as collagen deposition, were investigated in 100 liver specimens from patients with varying degree of hepatitis B virus (HBV)-related fibrosis. Human primary HSCs and the immortalized cell line (LX2 cells) were used for functional studies. We found that miR-942 expression was upregulated in activated HSCs and correlated inversely with BAMBI expression in liver fibrosis progression. Transforming growth factor beta (TGF-ß) and lipopolyssacharide (LPS), two major drivers of liver fibrosis and inflammation, induce miR-942 expression in HSCs via Smad2/3 respective NF-κB/p50 binding to the miR-942 promoter. Mechanistically, the induced miR-942 degrades BAMBI mRNA in HSCs, thereby sensitizing the cells for fibrogenic TGF-ß signaling and also partly mediates LPS-induced proinflammatory HSC fate. In conclusion, the TGF-ß and LPS-induced miR-942 mediates HSC activation through downregulation of BAMBI in human liver fibrosis. Our study provides new insights on the molecular mechanism of HSC activation and fibrosis.

Xia-Yu-Xue Decoction Inhibits Intestinal Epithelial Cell Apoptosis in CCl4-Induced Liver Fibrosis.

BACKGROUND/AIMS: Intestine-derived endotoxin is thought to play a role in the development of liver fibrosis. However, the pathological change in the intestine during liver fibrosis is still poorly understood. Here, we investigated the effects of Xia-yu-xue decoction (XYXD) on intestinal inflammation, apoptosis, and tight junction integrity in the carbon tetrachloride (CCl4)-induced liver fibrosis. METHODS: Murine liver fibrosis was developed by CCI4 treatment three times per week over a 6-week period. The CCl4-treated mice were divided into two groups: the CCl4-water group (n=8, CCl4) and the CCl4-XYXD group (n=8, CCl4+XYXD). The CCl4+XYXD mice were treated with XYXD from the beginning of the first week. The expression of inflammatory cytokines and apoptotic molecules were examined using immunohistochemistry, real-time PCR, and western blot. The intestinal epithelial cell apoptosis was examined by TUNEL staining. The tight junction-related molecules, such as ZO-1, claudin, and occludin in the gut were measured by real-time PCR. RESULTS: In CCl4-treated mice damage of the intestinal epithelia and infiltration of inflammatory cells into the lamina propria and muscular layer were observed. Proinflammatory markers MCP-1, TNF-α, CXCL11, IL-6, and CD68 were significantly increased in the intestinal epithelia in CCI4-treated mice. The expression of pro-apoptotic molecules including Fas and Bax was increased in the intestinal epithelia in CCI4-treated mice compared with that in control. The number of TUNEL-positive intestinal epithelial cells was also markedly increased in CCl4-treated mice. The expression of the tight junction proteins including ZO-1, claudin, and occludin was significantly decreased in CCI4-treated mice compared with that in control mice. Notably, XYXD treatment ameliorated increased inflammatory markers and apoptosis-related molecules and decreased tight-junction proteins in CCl4-treated mice. CONCLUSION: CCl4-treatment increased expression of proinflammatory cytokines and pro-apoptotic molecules and disrupted tight junction integrity in the intestine. XYXD treatment ameliorated intestinal inflammation, cell death, and tight junction disintegrity induced by CCl4 treatment, suggesting that XYXD inhibits CCl4-mediated liver fibrosis at least in part by ameliorating the intestinal epithelial damage.

Phytoremediation of diphenylarsinic-acid-contaminated soil by Pteris vittata associated with Phyllobacterium myrsinacearum RC6b.

A pot experiment was conducted to explore the phytoremediation of a diphenylarsinic acid (DPAA)-spiked soil using Pteris vittata associated with exogenous Phyllobacterium myrsinacearum RC6b. Removal of DPAA from the soil, soil enzyme activities, and the functional diversity of the soil microbial community were evaluated. DPAA concentrations in soil treated with the fern or the bacterium were 35-47% lower than that in the control and were lowest in soil treated with P. vittata and P. myrsinacearum together. The presence of the bacterium added in the soil significantly increased the plant growth and DPAA accumulation. In addition, the activities of dehydrogenase and fluorescein diacetate hydrolysis and the average well-color development values increased by 41-91%, 37-78%, and 35-73%, respectively, in the treatments with P. vittata and/or P. myrsinacearum compared with the control, with the highest increase in the presence of P. vittata and P. myrsinacearum together. Both fern and bacterium alone greatly enhanced the removal of DPAA and the recovery of soil ecological function and these effects were further enhanced by P. vittata and P. myrsinacearum together. Our findings provide a new strategy for remediation of DPAA-contaminated soil by using a hyperaccumulator/microbial inoculant alternative to traditional physicochemical method or biological degradation.

Sorafenib Inhibits Renal Fibrosis Induced by Unilateral Ureteral Obstruction via Inhibition of Macrophage Infiltration.

AIMS: Sorafenib, which has been used extensively for the treatment of renal cell cancer and advanced hepatocellular carcinoma (HCC), has also been shown to have antifibrotic effects in liver fibrosis. However, the effects of sorafenib on renal fibrosis are unknown. Therefore, we investigated whether sorafenib inhibited renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) and further explored the potential mechanism. METHODS: Mice underwent UUO followed by vehicle or sorafenib treatment. The expression of CD68, a macrophage marker, and the pro-inflammatory cytokines, MCP1 and CXCR3, were immunohistochemically analyzed. The involvement of macrophages in the formation of renal fibrosis was studied using confocal microscopy. RESULTS: Renal histopathology improved in the UUO-sorafenib mice. Sorafenib notably suppressed TGF-ß1-mediated renal fibrogenic effects. The mRNA and protein expressions of CD68, MCP1, and CXCR3 in the obstructed kidney were significantly decreased by sorafenib. Immunohistochemistry showed that CD68 and CXCR3 had a similar distribution, whereas MCP1 was observed predominantly in the tubular epithelial cells. Double immunofluorescence demonstrated that CD68-positive macrophages could co-localize with CXCR3. It also revealed that CXCR3 interacted with CXCL11 in the UUO mouse kidneys. Widespread adhesion of macrophages to myofibroblasts was markedly inhibited in UUO-sorafenib mouse kidneys. CONCLUSIONS: Taken together, the results indicated that sorafenib had protective effects against renal fibrosis; its mechanism of action was associated with inhibition of macrophage infiltration via the CXCR3/CXCL11 pathway. These data suggest the clinical potential of sorafenib for treatment of renal fibrosis and illustrate the immunological mechanisms underlying the protective effects of sorafenib.

IFIH1-mediated post-transcriptional regulation of PTTG1 promotes proliferation and affects PHA-848125 sensitivity and prognosis in oropharyngeal carcinoma.

The pituitary tumor-transforming gene 1 (PTTG1) is an oncogene involved in chromosomal segregation, DNA repair, apoptosis, and metabolism. PTTG1 can be used for clinical diagnosis and treatment and is a potential target for oropharyngeal carcinoma. The proliferation and viability of Cal27 and FaDu cells were assessed using the CCK-8 assay. Real-time PCR and western blotting, respectively, were used to analyze the mRNA and protein expression levels of PTTG1 and IFIH1. The interaction between PTTG1 mRNA and the translational regulatory protein IFIH1 was analyzed using RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays. PTTG1 protein was significantly overexpressed in oropharyngeal carcinoma, whereas PTTG1 mRNA was not. We hypothesized that a translation regulatory protein plays a post-transcriptional role in PTTG1. The IFIH1 protein specifically bound to the 42-52 nt region of PTTG1 mRNA, promoted the translation of PTTG1, and promoted the proliferation of oropharyngeal cancer cells. Administration of the PTTG1 inhibitor PHA-848125 and silencing of IFIH1 synergistically decreased the expression of PTTG1, inhibited the proliferation of oropharyngeal cancer cells, and indicated a good prognosis. We found that the IFIH1-PTTG1 axis could regulate the PHA-848125 response and functionally mediate inter-individual oropharyngeal cancer susceptibility and prognosis. This study aimed to confirm the upstream regulatory genes of PTTG1 and further investigate the specific interactions in this signaling pathway, which will provide a new approach for the treatment of oropharyngeal carcinoma.

Application of ultrasound elastography and radiomic for predicting central cervical lymph node metastasis in papillary thyroid microcarcinoma.

Objective: This study aims to combine ultrasound (US) elastography (USE) and radiomic to predict central cervical lymph node metastasis (CLNM) in patients with papillary thyroid microcarcinoma (PTMC). Methods: A total of 204 patients with 204 thyroid nodules who were confirmed with PTMC and treated in our hospital were enrolled and randomly assigned to the training set (n = 142) and the validation set (n = 62). US features, USE (gender, shape, echogenic foci, thyroid imaging reporting and data system (TIRADS) category, and elasticity score), and radiomic signature were employed to build three models. A nomogram was plotted for the combined model, and decision curve analysis was applied for clinical use. Results: The combined model (USE and radiomic) showed optimal diagnostic performance in both training (AUC = 0.868) and validation sets (AUC = 0.857), outperforming other models. Conclusion: The combined model based on USE and radiomic showed a superior performance in the prediction of CLNM of patients with PTMC, covering the shortage of low specificity of conventional US in detecting CLNM.

Integrated and effective management of muck waste under the platform governance mode for a circular economy.

As an inevitable part of construction and demolition (C&D) waste, muck has a dreadful environmental impact due its inadequate management by the traditional governance process. This paper therefore focuses on the management of muck generated from C&D waste by utilizing platform governance as an alternative process, which should more effectively contribute to China's circular economy. The study explores the feasibility of providing such a platform governance mode by using Petri net to compare the traditional governance process and platform governance process for the management of muck trucks, and by using Nanjing's muck smart supervision platform as a case study to assess the effectiveness of the platform governance mode. Results from Petri net simulation modeling reveal that the platform governance mode is more effective than the traditional mode, and from the case study it is found that the success of Nanjing's muck waste management can be attributed to the platform governance mode. The platform management approach can therefore contribute to the sustainability of muck waste governance, and is suitable as an integrated and effective management mode for current practices of muck waste management and resource recovery in China. The main finding from the study is that the platform governance mode significantly improves the efficiency of muck waste management as compared with the traditional governance mode and can therefore provide greater economic and environmental benefits as part of a circular economy.

Effects of Scallop Mantle Toxin on Intestinal Microflora and Intestinal Barrier Function in Mice.

Previous studies have shown that feeding mice with food containing mantle tissue from Japanese scallops results in aggravated liver and kidney damage, ultimately resulting in mortality within weeks. The aim of this study is to evaluate the toxicity of scallop mantle in China's coastal areas and explore the impact of scallop mantle toxins (SMT) on intestinal barrier integrity and gut microbiota in mice. The Illumina MiSeq sequencing of V3-V4 hypervariable regions of 16S ribosomal RNA was employed to study the alterations in gut microbiota in the feces of SMT mice. The results showed that intestinal flora abundance and diversity in the SMT group were decreased. Compared with the control group, significant increases were observed in serum indexes related to liver, intestine, inflammation, and kidney functions among SMT-exposed mice. Accompanied by varying degrees of tissue damage observed within these organs, the beneficial bacteria of Muribaculaceae and Marinifilaceae significantly reduced, while the harmful bacteria of Enterobacteriaceae and Helicobacter were significantly increased. Taken together, this article elucidates the inflammation and glucose metabolism disorder caused by scallop mantle toxin in mice from the angle of gut microbiota and metabolism. SMT can destroy the equilibrium of intestinal flora and damage the intestinal mucosal barrier, which leads to glucose metabolism disorder and intestinal dysfunction and may ultimately bring about systemic toxicity.